Neurotransmission mediated by N-methyl-D-aspartate (NMDA) receptors is essential for the basic brain development and function (Traynelis et al., 2010). These glutamate receptors predominantly control synaptic plasticity and memory function. NMDA receptors form heteromeric ion channels and activate upon concurrent binding of glycine and glutamate to the GluN1 and GluN2 subunits, respectively. Their ion channel activity is allosterically regulated by binding of small compounds to the amino terminal domain (ATD) in a subtype specific manner.
Since the unexpected discovery that the anti-hypertensive agent, ifenprodil, has neuroprotective effect through NMDA receptors (Gotti et al., 1988), enormous effort has been made to understand the mechanism of its pharmacological action of and to improve compound design for therapeutic purposes (Hansen et al., 2010; Mony et al., 2009). Despite such studies, the structural determinants responsible for NMDA receptor subunit selectivity have not been identified. Consequently, the design and development of additional therapeutic phenylethanolamine-based compounds for use as neuroprotectants have been limited.